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DEVELOPMENT on August 6, 2019 CELL BY CELL With a trio of techniques, scientists are tracking embryo development in stunning detail By Elizabeth Pennisi

rom at least the time of Hippocrates, timately orchestrates the processes by which in stunning detail, cell by cell and through biologists have been transfixed by cells multiply and specialize. Now, just as a time. is recognizing that combination the mystery of how a single cell de- music score indicates when strings, brass, of technologies, and its potential for spurring velops into an adult animal with percussion, and woodwinds chime in to cre- advances in basic research and medicine, as multiple organs and billions of cells. ate a symphony, a combination of techno- the 2018 . The ancient Greek physician hypoth- logies is revealing when genes in individual Driving those advances are techniques esized that moisture from a mother’s cells switch on, cueing the cells to play their for isolating thousands of intact cells from breath helps shape a growing infant, specialized parts. The result is the ability to living organisms, efficiently sequencing ex-

but now we know it is DNA that ul- track development of organisms and organs pressed genetic material in each cell, and YIQUN AND FARRELL JEFFREY IMAGE: UNIVERSITY LAB/HARVARD WANG/SCHIER

F1344 21 DECEMBER 2018 • VOL 362 ISSUE 6421 sciencemag.org SCIENCE

Published by AAAS A representation of cell lineages in a zebrafish embryo, had been cut into pieces. The scientists dis- color-coded by time. The first cells are gray; covered new cell types and developmental by 6 hours (gold), three major branches have formed. trajectories that emerged as each piece re- PEOPLE’S CHOICE grew into a whole individual. Another group Our readers weigh in with their picks using computers, or labeling the cells, to traced the genes that switched on and off in for the top breakthrough of 2018 reconstruct their relationships in space and axolotls, a type of salamander, that had lost time. That technical trifecta “will transform a forelimb. The researchers found that some Visitors to Science’s website are the next decade of research,” says Nikolaus mature limb tissue reverted to an embryonic, in agreement with the magazine’s Rajewsky, a systems biologist at the Max undifferentiated state and then underwent reporters and editors: Development cell Delbrück Center for Molecular Medicine in cellular and molecular reprogramming to by cell is the Breakthrough of the Year. Berlin. This year alone, papers detailed how build a new limb. We invited online readers to a flatworm, a fish, a frog, and other organ- Because cells must be removed from an vote on a dozen candidates for the isms begin to make organs and appendages. organism for single-cell sequencing, that breakthrough. The first round of voting And groups around the world are applying technique alone can’t show how those cells narrowed the choices to four, and a the techniques to study how hu- interact with their neighbors or second round, in which more than man cells mature over a lifetime, ON OUR WEBSITE identify the cells’ descendants. 12,000 votes were cast, determined how tissues regenerate, and how But by engineering markers into the top People’s Choice. For more on the cells change in diseases. Breakthrough of early embryonic cells, research- The combination of techniques The ability to isolate thousands the Year, including ers can now track cells and their that enables scientists to track of individual cells and sequence a video and a progeny in living organisms. At development at the cellular level, podcast, go to: Downloaded from each one’s genetic material gives https://scim.ag/ least one team exposes early em- in stunning detail and over time, was researchers a snapshot of what Breakthrough2018 bryos to mobile genetic elements the clear winner. The approval of a RNA is being produced in each cell that carry genes for different gene-silencing drug after 20 years at that moment. And because RNA sequences colored fluorescent tags, which randomly of development took second place, are specific to the genes that produced them, settle into the cells, imparting different col- followed by the detection of a neutrino researchers can see which genes are active. ors to each cell lineage. Other teams have traced to a source outside our galaxy. Those active genes define what a cell does. harnessed the gene-editing technique called The fourth contender, a set of images http://science.sciencemag.org/ That combination of techniques, known CRISPR to mark the genomes of individual of the fruit fly brain showing individual as single-cell RNA-seq, has evolved over the cells with unique barcodelike identifiers, synapses, just missed Science’s top 10. past few years. But a turning point came which are then passed on to all their de- last year, when two groups showed it could scendants. The gene editor can make new 1 Development cell by cell 35% be done on a scale large enough to track mutations in progeny cells while retaining early development. One group used single- the original mutations, enabling scientists 2 RNAi drug approved 30% cell RNA-seq to measure gene activity in 8000 to track how lineages branch off to form cells extracted at one time point from fruit fly new cell types. 3 Neutrinos from a blazar 23% embryos. About the same time, another team By combining those techniques with sin- 4 Fly brain revealed 12%

profiled gene activity of 50,000 cells from one gle-cell RNA-seq, researchers can both moni- on August 6, 2019 larval stage of the nematode Caenorhabditis tor the behavior of individual cells and see elegans. The data indicated which proteins, how they fit into the organism’s unfolding called transcription factors, were guiding the architecture. Using that approach, one team to identify every human cell type, where each cells to differentiate into specialized types. determined the relationships of more than type is located in the body, and how the cells This year, those researchers and others 100 cell types in zebrafish brains. The re- work together to form tissues and organs. performed even more extensive analyses on searchers used CRISPR to mark early em- Already, one project has identified most, if vertebrate embryos. Using a variety of sophis- bryonic cells, then isolated and sequenced not all, kidney cell types, including ones that ticated computational methods, they linked 60,000 cells at different time points to track tend to become cancerous. Another effort single-cell RNA-seq readouts taken at differ- gene activity as the fish embryo developed. has revealed the interplay between maternal ent time points to reveal the turning on and Other groups are applying similar tech- and fetal cells that allows pregnancy to pro- off of sets of genes that defined the types of niques to track what happens in developing ceed. And a collaboration of 53 institutions cells formed in those more complex organ- organs, limbs, or other tissues—and how and 60 companies across Europe, called the isms. One study uncovered how a fertilized those processes can go wrong, resulting in LifeTime consortium, is proposing to har- zebrafish egg gives rise to 25 cell types; an- malformations or disease. “It’s like a flight ness single-cell RNA-seq in a multipronged other monitored frog development through recorder, where you are watching what went effort to understand what happens cell by early stages of organ formation and deter- wrong and not just looking at a snapshot at cell as tissues progress toward cancer, diabe- mined that some cells begin to specialize ear- the end,” says Jonathan Weissman, a stem tes, and other diseases. lier than previously thought. “The techniques cell biologist at the University of California, High-resolution movies of development have answered fundamental questions re- San Francisco. “We can ask questions at a and disease will only get more compelling. garding embryology,” says Harvard Univer- resolution that was just not possible before.” Papers already posted online extend devel- sity biologist Leonard Zon. Although those technologies cannot be opment studies to ever-more-complex or- Researchers interested in how some ani- used directly in developing human embryos, ganisms. And researchers hope to combine mals can regrow limbs or whole bodies have researchers are applying the approaches to single-cell RNA-seq with new microscopy also turned to single-cell RNA-seq. Two human tissues and organoids to study gene techniques to see where in each cell its dis- groups studied gene expression patterns in activity cell by cell and characterize cell tinctive molecular activity takes place and aquatic flatworms called planaria—among types. An international consortium called how neighboring cells affect that activity. biology’s champion regenerators—after they the Human Cell Atlas is 2 years into an effort The single-cell revolution is just starting. j

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